Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase‐9 activation through a calcium and protein kinase Cα‐dependent pathway: phorbol‐12‐myristate‐13‐acetate‐induced/extracellular signal‐regulated kinase/activator protein‐1

Abstract

Background and purpose:Population studies have revealed that treatment with the anti-diabetic drug metformin is significantly associated with reduced cancer risk, but the underlying mode of action has not been elucidated. The aim of our study was to determine the effect of metformin on tumour invasion and migration, and the possible mechanisms, using human fibrosarcoma HT-1080 cells. Experimental approach: We employed invasion, migration and gelatin zymography assays to characterize the effect of metformin on HT-1080 cells. Transient transfection assays were performed to gene promoter activities, and immunoblot analysis to study its molecular mechanisms of action. Key results: Metformin inhibited migration and invasion by HT-1080 cells at sub-toxic concentrations. In these cells, metformin also suppressed phorbol-12-myristate-13-acetate (PMA)-enhanced levels of matrix metalloproteinases-9 (MMP-9) protein, mRNA and transcription activity through suppression of activator protein-1 (AP-1) activation. In addition, metformin strongly repressed the PMA-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and protein kinase C(PKC)a, whereas the phosphorylation of p38 mitogen-activated protein kinase was not affected by metformin. Metformin decreased the PMA-induced Ca 2+ influx. Furthermore, treatment with an intracellular Ca 2+ chelator (BAPTA-AM) or a selective calmodulin antagonist (W7) markedly decreased PMA-induced MMP-9 secretion and cell migration, as well as activation of ERK and JNK/AP-1. Conclusions and implications: Metformin inhibited PMA-induced invasion and migration of human fibrosarcoma cells via Ca 2+-dependent PKCa/ERK and JNK/AP-1-signalling pathways. Metformin therefore has the potential to be a potent anti-cancer drug in therapeutic strategies for fibrosarcoma metastasis.

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

“…The mode of action and the biologic consequences of the antidiabetic drug metformin in cancer cell migration and invasion are poorly understood. Indeed, only few studies done in fibrosarcoma, carcinoma, and ovarian carcinoma cells evoke the role of metformin in this process (21)(22)(23). The current study was designed to evaluate the antiinvasive potential of metformin in melanoma and to analyze the molecular mechanisms involved in this process.…”

Cisplatin Combined with Metformin Inhibits Migration and Invasion of Human Nasopharyngeal Carcinoma Cells by Regulating E-cadherin and MMP-9

“…However, the mode of action and the biological consequences of the anti-diabetic drug, metformin, in cancer cell migration and invasion are poorly understood. Indeed, only a few studies performed in fibrosarcoma, carcinoma, and ovarian carcinoma cells have addressed the role of metformin in this process (Hwang et al, 2010;Tan et al, 2011;Wu et al, 2012), and the effects of metformin on invasion by NPC remain unknown. In our study, we found that metformin could enhance the effects of cisplatin on proliferation and invasion of human NPC cells.…”

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

“…This migration is a complex biologic process orchestrated by environmental factors, signal transduction, and cytoskeletal rearrangement. Several studies demonstrated that metformin exerts an antimigratory effect on cancer cells; however, its mechanism of action remains largely unknown (8)(9)(10)(11)(12)(13). In addition, how metformin interferes with the small GTPase Rac1, one of a master regulator of cell migration, is not known.…”